Abstracts

Induction of HBcAg-Specific CTL Responses by a Heat Shock Protein Fused to the Core Antigen of the Hepatitis B Virus

Abstract presented at 5th Annual Conference on Vaccine Research - Baltimore, MD, USA - May 6-8, 2002

Anthony L.S.D.; Liu H., Rowse G.; Wu B., Recktenwald A.; Mizzen L.A.; Boux H. and Siegel M.I. (2)

Stressgen Biotechnologies Corporation, Victoria, BC, Canada
2) Stressgen Biotechnologies, Inc., Collegeville, PA, USA

Individuals acutely infected with hepatitis B virus (HBV) typically recover from infection and exhibit strong, broadly specific CD8+ CTL responses, while chronically infected patients display relatively weak, narrowly focused responses. Resolution of chronic hepatitis may be induced by immunotherapy that primes effective HBV-specific CTL responses. Heat shock protein (Hsp) fusion proteins have been shown to prime potent CTL activity in experimental animals. We generated recombinant fusion proteins containing sequences from the HBV core antigen (HBc) and the 65 kDa Hsp from Mycobacterium bovis BCG. Spleen cells from mice immunized without exogenous adjuvant were restimulated with HBc-derived CTL epitope peptides. Cells from fusion protein-primed mice exhibited a high degree of lytic activity, whereas cells from mice immunized with HBc antigen alone displayed poor target cell lysis. The lytic activity was specific for multiple CTL epitopes, including an HLA-A2-restricted epitope. Effector cells lysed both peptide-pulsed target cells and also target cells transfected to express endogenous HBc antigen. The CTL released IFN-g and TNF-a, cytokines thought to be involved in inhibition of hepatic viral gene expression. In comparison with control mice, Tlr4 deficient C57BL/10ScNCr mice responded relatively poorly to fusion protein immunization, indicating that CTL priming is dependent, at least in part, upon this toll-like receptor. The results of these experiments clearly demonstrate the potential value of Hsp fusion proteins in the immunotherapy of chronic HBV hepatitis.